DESCRIPTION: The protective immune response operative in tuberculous infection is not completely defined. Nevertheless, it is generally accepted that Thi-mediated immunity plays a significant role in engendering protection against M. tuberculosis. This notion is perhaps best supported by the fact that HI V-infected individuals, in whom Thi cell apoptosis occurs, are highly susceptible to the tubercie bacillus. Emerging evidence suggests that apoptosis of T cells, including the Thi subtype. occurs during tuberculous infection. Our laboratory has recently observed that Th1 and Th2 cells can be differentially modulated to undergo apoptosis. We previously reported that CD95-meidated apoptosis in response to CD3/TCR (T cell receptor complex) ligation is observed only in Thi, and not in Th2 T cell clones. In contrast to Th2 lymphocytes, Thi cells demonstrated a distinct requirement for costimulation via ligation of specific T cell surface components with co-stimulatory molecules of antigen presenting cells such as macrophages. in addition to CD3 signals, to resist CD95-mediated apoptosis. This difference in sensitivity to apoptosis of the two Th subsets is due to selective upregulation of phosphatidylinositol 3'-kinase (PI3"-K) activity in Th2 clones following CD3 ligation. The upregulation of PI3'-K activity abrogates apoptosis by inhibiting CD95 aggregation in the membrane thereby blocking subsequent activation of the death effector molecule. caspase-S. Thus, activation of Thl cells, in a manner akin to antigen stimulation in the absence of co-stimulation, results in their apoptosis. Importantly, we have observed that expression of the B7 co-stimulatory molecule is down-regulated in M. tuberculosis-infected macrophages. Based on these observations. we propose to test the hypotheses that i,) in tuberculous infection, CD95-mediated Thi depletion occurs, resulting in attenuation of protective immunity against M. tuberculosis, thereby enhancing disease susceptibility; ii) downregulation of the expression of the B 7 class of costimulalory molecules contributes to Thi apoptosis. It is hoped that elucidation of the mechanisms underlying CD95-mediated Thi death in tuberculosis will help develop strategies to enhance protective immunity against the tubercle bacillus via specific disengagement of the apoptosis machinery in ThI cells.